tbuckley/cabot-search huggingface dataset:
SURG-08. 5-Aminolevulinic acid (5-ALA)-guided resection of pediatric brain tumors
Authors: Michael Schwake, Ann-Katrn Bruns, Michael Müther, Walter Stummer
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: 5-Aminolevulinic acid (5-ALA)-guided resection of gliomas in adults enables better differentiation between tumor and normal brain, allowing a higher degree of resection, and improved patient outcomes. In recent years, several reports have emerged regarding the use of 5-ALA in other brain tumor entities, including pediatric brains tumors. Since gross total resection (GTR) of many brain tumors in children is crucial, the role of 5-ALA-guided resection requires elucidation. METHODS: A systematic literature review of EMBASE and MEDLINE/PubMed databases revealed 20 eligible publications encompassing 186 5-ALA-guided operations on pediatric brain tumors. To reduce bias, publications were revised independently by two authors. RESULTS: 5-ALA-guided resection enabled the surgeons to identify the tumor more easily and was considered helpful mainly in cases of glioblastoma (GBM, 21/27, 78%), anaplastic ependymoma WHO grade III (10/14, 71%), and anaplastic astrocytoma (4/6, 67%). In contrast, cases of pilocytic astrocytomas (PAs) and medulloblastomas 5-ALA-guided surgery did not show consistent fluorescent signals and 5-ALA was considered helpful only in 12% and 22% of cases, respectively. Accumulation of fluorescent porphyrins seems to depend on WHO tumor grading. In case fluorescence signal was considered helpful, it was associated to a greater degree of resection. One study showed an association between visible fluoresce signal and concentration of protopophyrin IX (PPIX) concentration. A threshold of 4μg/ml was required in order to visualize the fluorescence signal. The rate of adverse events related to 5-ALA was negligible, especially new postoperative sequelae. CONCLUSION: 5-ALA could play a role in resection of malignant, contrast enhancing, supratentorial pediatric brain tumors. At present, we are conducting a prospective phase I-II multicenter clinical trial to evaluate side effects and feasibility of 5-ALA guided surgery
Operational metrics for the ELAINE II study combining a traditional approach with a just-in-time model.
Authors: Sibel Blau, Julio Antonio Peguero, Halle C. F. Moore, Ian Churchill Anderson, Minal A. Barve, Mathew Amprayil Cherian, Ahmed Elkhanany, Ciara Catherine Maria O'Sullivan, Alvaro Moreno-Aspitia, Paul Plourde, Lyon L. Gleich, Kendra Riesen, Ross Ezzati, Meghan Degele, Megan Shulman, Stephanie Stempf, Matthew M. Cooney, Senthil Damodaran
Journal: Journal of Clinical Oncology (2022)

1504 Background: Trial recruitment that requires specific actionable mutations based on next-generation sequencing (NGS) is challenging. Barriers can include competing studies, physician study awareness, site proximity, mutation incidence, among other concerns. Methods: This study (NCT04432454) opened clinical sites using two methods during the COVID-19 pandemic. The “Traditional” approach included site selection, IRB and contract approval, and trial activation prior to a patient being identified for enrollment. The second approach used the Tempus “TIME” Trials network that would only open a site after identifying a patient with a mutation of interest and eligible for the trial. Results: The first patient enrolled was on 10/12/20 and the last patient was on 6/24/21. A total of 16 sites (6 Traditional and 10 TIME) participated. All Traditional sites, and none of the TIME sites, were affiliated with major academic institutions. Duration for full CTA execution for Traditional sites averaged 200.5 days (range 142 to 257) and for TIME sites averaged 7.6 days (range 2 to 14). IRB approval time average for Traditional sites was 27.5 days (range 12 to 71) and TIME sites was 3.0 days (range 1 to 12 days). Days from site selection to activation letter for Traditional sites was on average 250.0 days (range 187 to 281) and for TIME sites was 131.6 days (range 22 to 248). Time from study activation to first consent was 33.3 days (range 18 to 58) for Traditional sites and 8.8 days (range 1 to 35) for TIME sites. The first patient on-study was at a TIME site 115 days prior to a Traditional site and the first 7 patients enrolled were at TIME sites. Traditional sites consented 23 and enrolled 16 patients while the TIME sites consented 16 and enrolled 13. The trial enrolled all 29 patients in 8 months with the anticipated enrollment duration being 12 to 18 months. Conclusions: Although the Traditional and TIME programs had different operational models, they both contributed a significant number of patients and reduced the projected enrollment timeline. TIME sites enrolled the initial patients. These results demonstrate that the “Just-in-Time model,” in conjunction with a Traditional model, can reduce projected overall time to enrollment in biomarker-driven studies. [Table: see text]
Endothelial Cells Induced Progenitors Into Brown Fat to Reduce Atherosclerosis
Authors: Kyoungmin Park, Qian Li, Matthew D. Lynes, Hisashi Yokomizo, Ernesto Maddaloni, Takanori Shinjo, Ronald St-Louis, Qin Li, Sayaka Katagiri, Jialin Fu, Allen Clermont, Hyunseok Park, I-Hsien Wu, Marc Gregory Yu, Hetal Shah, Yu-Hua Tseng, George L. King
Journal: Circulation Research (2022)

Insulin resistance (IR) can increase atherosclerotic and cardiovascular risk by inducing endothelial dysfunction, decreasing nitric oxide (NO) production, and accelerating arterial inflammation. The aim is to determine the mechanism by which insulin action and NO production in endothelial cells can improve systemic bioenergetics and decrease atherosclerosis via differentiation of perivascular progenitor cells (PPCs) into brown adipocytes (BAT).Studies used various endothelial transgenic and deletion mutant ApoE-/- mice of insulin receptors, eNOS (endothelial NO synthase) and ETBR (endothelin receptor type B) receptors for assessments of atherosclerosis. Cells were isolated from perivascular fat and micro-vessels for studies on differentiation and signaling mechanisms in responses to NO, insulin, and lipokines from BAT.Enhancing insulin's actions on endothelial cells and NO production in ECIRS1 transgenic mice reduced body weight and increased systemic energy expenditure and BAT mass and activity by inducing differentiation of PPCs into beige/BAT even with high-fat diet. However, positive changes in bioenergetics, BAT differentiation from PPCs and weight loss were inhibited by N(gamma)-nitro-L-arginine methyl ester (L-NAME), an inhibitor of eNOS, in ECIRS1 mice and eNOSKO mice. The mechanism mediating NO's action on PPC differentiation into BAT was identified as the activation of solubilized guanylate cyclase/PKGIα (cGMP protein-dependent kinase Iα)/GSK3β (glycogen synthase kinase 3β) pathways. Plasma lipidomics from ECIRS1 mice with NO-induced increased BAT mass revealed elevated 12,13-diHOME production. Infusion of 12,13-diHOME improved endothelial dysfunction and decreased atherosclerosis, whereas its reduction had opposite effects in ApoE-/-mice.Activation of eNOS and endothelial cells by insulin enhanced the differentiation of PPC to BAT and its lipokines and improved systemic bioenergetics and atherosclerosis, suggesting that endothelial dysfunction is a major contributor of energy disequilibrium in obesity.
Risankizumab as induction therapy for Crohn's disease: results from the phase 3 ADVANCE and MOTIVATE induction trials
Authors: Geert D'Haens, Remo Panaccione, Filip Baert, Peter Bossuyt, Jean-Frederic Colombel, Silvio Danese, Marla Dubinsky, Brian G Feagan, Tadakazu Hisamatsu, Allen Lim, James O Lindsay, Edward V Loftus, Julian Panés, Laurent Peyrin-Biroulet, Zhihua Ran, David T Rubin, William J Sandborn, Stefan Schreiber, Ezequiel Neimark, Alexandra Song, Kristina Kligys, Yinuo Pang, Valerie Pivorunas, Sofie Berg, W Rachel Duan, Bidan Huang, Jasmina Kalabic, Xiaomei Liao, Anne Robinson, Kori Wallace, Marc Ferrante
Journal: The Lancet (2022)
Project facilitate: Innovation and advancement in FDA’s oncology expanded access program.
Authors: Mitchell Chan, Ramya Antony, Jessica Boehmer, Tamy Kim, Richard Pazdur
Journal: Journal of Clinical Oncology (2022)

e18556 Background: FDA Oncology Center of Excellence’s (OCE) Project Facilitate (PF) was launched in June 2019 in response to perceived barriers providers face when accessing Expanded Access (EA). Since launch, PF continues to evolve and innovate to provide a comprehensive service to assist oncology healthcare providers requesting EA. An analysis of single-patient investigational new drugs (IND) was performed over 1 year to assess the growth and impact of the program. Methods: Data was extracted from Project Facilitate’s central database that yielded 640 single-patient INDs between June 1, 2020 and June 1, 2021. Data collected included IND receipt date, granting date, status, application type, indication, drug name, address of requestor, and patient demographics. Results: Of the 640 single-patient INDs extracted, there were 183 emergency INDs (eIND) and 457 non-emergency INDs (SPI). EA requests originated primarily from academic centers (81%) and community hospitals (18%) whereas Veterans Affairs and Military Treatment Facilities (0.5%) and Other (0.5%) were the least common. The 5 most common states requests originated from include New York (14%), California (13%), Texas (11%), Pennsylvania (7%), and North Carolina (4%). Although the current FDA Form 3926 does not request race and ethnicity information, this data was reported in 17 requests: White (8), Asian (3), Black/African American (3), American Indian or Alaskan Native (0), Native Hawaiian or Other Pacific Islander (0), Hispanic or Latino (3) and non-Hispanic or Latino (0). Age distribution was analyzed for pediatric (24%) and adult (76%) patients. Age distribution was further analyzed in geriatrics &gt;75 (10%), in pediatrics &lt; 2 (7%) and patients 2-17 years old (17%). The processing and review times for 630 applications were &lt;1 day (96%) and &gt; 1 day (4%). PF granted 100% of EA requests received in this time period. PF’s call center received 525 phone calls of which 499 (95%) were answered on the first call. PF also received 7843 emails during this period. Conclusions: Since 6/1/2020, PF started performing the reviews, processing and granting of CDER oncology EA requests that generally were performed by the FDA Review Divisions. By consolidating this process to PF, review times have drastically reduced to &lt;1 day. PF has evolved since launch to promote effective and equal access to oncology expanded access.[Table: see text]
Ramucirumab as second-line treatment in patients with advanced hepatocellular carcinoma (HCC) and elevated alpha-fetoprotein (AFP) following first line sorafenib: Pooled efficacy and safety in Chinese patients across two global randomized phase 3 studies (REACH-2 and REACH).
Authors: Guoliang Shao, Yuxian Bai, Xiaoming Chen, Shanzhi Gu, Kangsheng Gu, Xianglin Yuan, Ryan C Widau, Wanli Zhang, Qiang Zhang, Shukui Qin
Journal: Journal of Clinical Oncology (2022)

e16081 Background: REACH-2 and REACH were two global, randomized, double-blind, placebo (PL)-controlled phase 3 studies of Ramucirumab (RAM) versus PL in patients with HCC after prior sorafenib. REACH-2 confirmed the RAM treatment benefit for patients with baseline AFP ≥ 400 ng/mL, consistent with results in a prespecified subgroup of patients in REACH with AFP ≥ 400 ng/mL. A pooled analysis was performed to evaluate the efficacy and safety of RAM in Chinese patients (including patients from mainland China, Hong Kong, and Taiwan) from REACH-2 and REACH with baseline AFP ≥400 ng/mL. Methods: Except for AFP level requirement, REACH-2 and REACH were similar in study design and included patients who had advanced HCC (BCLC stage C or B disease refractory or not amenable to locoregional therapy), Child-Pugh A, ECOG PS 0-1, and prior sorafenib. Patients were randomized to RAM (8 mg/kg) I.V. or PL Q2W, plus best supportive care, until disease progression or unacceptable toxicity. Individual patient data were pooled from REACH-2 and REACH (AFP ≥400 mg/mL). Overall survival (OS) and progression-free survival (PFS) were evaluated using Kaplan-Meier method and Cox proportional hazard model. Objective response rate (ORR), disease control rate (DCR), and safety were reported. Efficacy analyses were stratified by study to account for any potential difference in the two studies. Results: Data from 155 Chinese patients were pooled from REACH (51) and REACH-2 (104) (N = 98 RAM vs N = 57 PL). Baseline characteristics were generally balanced between arms in pooled data set; however, lower median level of AFP was noted in the RAM arm. In the pooled population, RAM treatment numerically improved OS over PL (median OS 7.1 months vs 4.7 months; HR = 0.735 [95% CI: 0.512, 1.055]). Improvements in PFS (median PFS 2.6 months vs 1.5 months; HR = 0.666 [95% CI: 0.459, 0.967]), ORR (3.1% vs 0%), and DCR (44.9% vs 29.8%) were also observed. Hypertension (6.1% vs 1.8%), pneumonia (5.1% vs 1.8%), and hyponatremia (5.1% vs 1.8%) were the Grade ≥3 treatment-emergent adverse events (TEAEs) among ≥ 5% patients that was more frequently observed in the RAM arm compared with the PL arm. Conclusions: Pooled analysis of two phase 3 trials of RAM as second-line treatment in patients with HCC following sorafenib demonstrated a clinically meaningful benefit with a manageable safety profile in Chinese HCC patients with baseline AFP ≥ 400 ng/mL. Treatment benefits in OS observed in the pooled Chinese population were consistent with the entire population from REACH/REACH-2 (AFP ≥ 400 ng/mL). Clinical trial information: NCT01140347, NCT02435433.
Cardiovascular Magnetic Resonance for Rejection Surveillance After Cardiac Transplantation
Authors: Chris Anthony, Muhammad Imran, Jim Pouliopoulos, Sam Emmanuel, James Iliff, Zhixin Liu, Kirsten Moffat, Min Ru Qiu, Catriona A. McLean, Christian Stehning, Valentina Puntmann, Vass Vassiliou, Tevfik F. Ismail, Ankur Gulati, Sanjay Prasad, Robert M. Graham, Jane McCrohon, Cameron Holloway, Eugene Kotlyar, Kavitha Muthiah, Anne M. Keogh, Christopher S. Hayward, Peter S. Macdonald, Andrew Jabbour
Journal: Circulation (2022)

Background: Endomyocardial biopsy (EMB) is the gold standard method for surveillance of acute cardiac allograft rejection (ACAR) despite its invasive nature. Cardiovascular magnetic resonance (CMR)–based myocardial tissue characterization allows detection of myocarditis. The feasibility of CMR-based surveillance for ACAR-induced myocarditis in the first year after heart transplantation is currently undescribed. Methods: CMR-based multiparametric mapping was initially assessed in a prospective cross-sectional fashion to establish agreement between CMR- and EMB-based ACAR and to determine CMR cutoff values between rejection grades. A prospective randomized noninferiority pilot study was then undertaken in adult orthotopic heart transplant recipients who were randomized at 4 weeks after orthotopic heart transplantation to either CMR- or EMB-based rejection surveillance. Clinical end points were assessed at 52 weeks. Results: Four hundred one CMR studies and 354 EMB procedures were performed in 106 participants. Forty heart transplant recipients were randomized. CMR-based multiparametric assessment was highly reproducible and reliable at detecting ACAR (area under the curve, 0.92; sensitivity, 93%; specificity, 92%; negative predictive value, 99%) with greater specificity and negative predictive value than either T1 or T2 parametric CMR mapping alone. High-grade rejection occurred in similar numbers of patients in each randomized group (CMR, n=7; EMB, n=8; P =0.74). Despite similarities in immunosuppression requirements, kidney function, and mortality between groups, the rates of hospitalization (9 of 20 [45%] versus 18 of 20 [90%]; odds ratio, 0.091; P =0.006) and infection (7 of 20 [35%] versus 14 of 20 [70%]; odds ratio, 0.192; P =0,019) were lower in the CMR group. On 15 occasions (6%), patients who were randomized to the CMR arm underwent EMB for clarification or logistic reasons, representing a 94% reduction in the requirement for EMB-based surveillance. Conclusions: A noninvasive CMR-based surveillance strategy for ACAR in the first year after orthotopic heart transplantation is feasible compared with EMB-based surveillance. Registration: HREC/13/SVH/66 and HREC/17/SVH/80. Australian New Zealand Clinical Trials Registry: ACTRN12618000672257.
LINC-04. Optic pathway gliomas in children: an 18-year experience in a middle-income country
Authors: Jorge Ramirez-Melo, Daniel Moreira, Ana Orozco-Alvarado, Fernando Sánchez-Zubieta, Regina Navarro-Martín del Campo
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: Optic pathway gliomas (OPGs) have favorable survival outcomes, but can have significant morbidity, from the tumor or from its treatment. This retrospective study sought to describe the clinical presentation and outcomes of children with OPGs at a tertiary center in a middle-income country. METHODS: Patients younger than 18 years diagnosed with OPGs between 2002-2020 at the Hospital Civil de Guadalajara in Mexico, were included. Survival analyses and logistic regression were used to determine risk factors for progression. RESULTS: Thirty patients were identified with a median age of six years. Common clinical characteristics at presentation included: visual accuracy impairment (40%), headache (23.3%), nystagmus (20%), endocrine disturbances (16.6%), and diencephalic syndrome (13%). Neurofibromatosis-1 was present in 23.3% of the patients. Eight patients underwent resection at diagnosis, 7 of them had secondary complications. One died during surgery due to catecholamine-resistant shock, and the other developed neuro-infection and died due to septic shock after surgery. Five children developed neurological or endocrine sequelae. Fifteen total patients received chemotherapy as their first line treatment. The 5-year progression-free survival was 77.9±10% and overall survival was 89.5±5%. Patients who received chemotherapy or targeted therapy as the first line of treatment had higher PFS compared to those who received other therapies (p=0.03). The patients who received surgery as first-line treatment had a 3.1 times greater risk of achieving a Lansky/Karnofsky score of fewer than 90 points 6 months after diagnosis (p=0.006). Ten patients had pre- and post-treatment ophthalmologic assessment, either visual acuity or visual evoqued potentials. Five had no changes and 5 showed improvement after treatment. CONCLUSIONS: These results show inferior outcomes compared to high-income countries, influenced importantly due to morbidity after surgical resection. These data can be used to prospectively optimize treatment at our institute and other middle-income countries through a multidisciplinary neuro-oncology team.
Correction: Targeting KDM6A Suppresses SREBP1c-Dependent Lipid Metabolism and Prostate Tumorigenesis
Authors: Donge Tang, Yong Dai, Songhui Xu
Journal: Cancer Research (2022)

The original version of this article (1) lists eight individuals as authors who attest that they were not aware of the submitted manuscript and did not agree to their authorship of it. The byline has been corrected in the latest online HTML and PDF versions of the article and the authors’ contributions have been updated as necessary.
Clinical outcomes of immune checkpoint inhibitors in <i>HER2-</i>amplified non-small cell lung cancers.
Authors: Raymond DeMatteo, Debra A. Goldman, Sabrina T. Lin, Darren J. Buonocore, JianJiong Gao, Jason C. Chang, Natasha Rekhtman, Michael Offin, Helena Alexandra Yu, James M. Isbell, David Randolph Jones, Charles M. Rudin, William D. Travis, Mark G. Kris, Alexander E. Drilon, Maria E. Arcila, Michelle S. Ginsberg, Alexia Iasonos, Dazhi Liu, Bob T. Li
Journal: Journal of Clinical Oncology (2022)

e21098 Background: HER2 (ERBB2) amplification is a distinct actionable oncogenic driver in 2-3% of non-small cell lung cancer (NSCLC). While HER2-targeted agents are now in development for lung cancers harboring HER2 mutations, the therapeutic landscape for patients with HER2 amplification is not well elucidated. Although immune checkpoint inhibitors (ICIs) alone or in combination with chemotherapy are widely used as treatment for NSCLC, little is known about the impact of ICIs in patients with HER2-amplified NSCLC. This study aimed to assess the efficacy of ICIs in this patient population. Methods: Patients with HER2-amplified NSCLC were identified from January 2014 to October 2021. HER2 amplification was detected by next generation sequencing (NGS) on the MSK-IMPACT platform. Clinicopathologic and molecular features, as well as response to therapy with ICIs were assessed. Patients were excluded if they harbored concurrent HER2 mutations, had localized disease, or received concurrent chemotherapy. Patient records were reviewed to evaluate overall survival (OS), progression free survival (PFS) and overall response rate (ORR). Results: Eighteen patients with metastatic HER2-amplified NSCLC who received ICI alone as first line treatment or subsequent therapy after progression met inclusion criteria. Histologic subtypes included adenocarcinoma (78%) and squamous cell carcinoma (22%). PD-L1 expression was available for 16 patients, with 69% having no expression of PD-L1. The median tumor mutation burden (TMB) was 9.2 mutations/Mb (range 3.0-35.4). The median OS was 11 months (95% CI: 4 to 37), with 6-month and 12-month survival being 67% (95% CI: 40% to 83%) and 49% (95% CI: 25% to 70%), respectively. Median PFS was 2 months (95% CI: 1 to 7). In the 15 patients that were assessed for response, the ORR was 0% (95% CI 0% to 19%), including 3 cases with PD-L1 expression of ≥ 50% and 9 cases with TMB ≥ 10 mutation/Mb. Conclusions: Patients with HER2-amplified NSCLC showed minimal response to immunotherapy, regardless of PD-L1 status and TMB. These findings underscore the importance of developing novel HER2-targeted agents for these patients with unmet medical need.
Camrelizumab combined with TIP (paclitaxel+cisplatin+ifosfamide) as neoadjuvant treatment of locally advanced penile cancer before lymphadenectomy: An exploratory, phase Ⅱ study.
Authors: Yongsheng Chen, Liangjun Wei, Lichen Teng, Yan Cao, Dechao Li, Wentao Wang, Hongxin Pan, Xingyuan Wang, Songlin Xu, Huang Wang, Yanjie Wang, Yuling Zhang, Changfu Li
Journal: Journal of Clinical Oncology (2022)

TPS5093 Background: Penile squamous cell carcinoma (PSCC) is a highly aggressive disease that accounts for 95% of penile cancers and is characterized by a high risk of early locoregional spread and morbidity with subsequent potential for distant dissemination. The lymph node invasion is one of the most important factor that affects the prognosis of PSCC. Penile cancer patients with uninvolved inguinal lymph nodes had a 5-year survival rate of 66% compared with 27% for those with involvement, and penile cancer with the pelvic lymph node involvement have a worse 5-year survival rate that is typically less than 10%. Therefore, this study aims to reduce small lesions to reach the radical lymphadenectomy by camrelizumab combined with TIP in the neoadjuvant treatment of PSCC. Methods: In this single-arm, prospective, phase Ⅱ study, 34 patients with histological or cytological diagnosis of locally advanced PSCC (TX, N2-N3, M0), ECOG performance score of 0-1, planned to be recruited. Enrolled patients with inguinal and/or pelvic lymph node metastasis (positive percutaneous lymph node biopsy) after primary tumor resection of penile cancer were treated with combined therapy including camrelizumab (200 mg, iv, Q3W), paclitaxel (175 mg/m 2 , iv, Q3W), cisplatin (25 mg/m 2 , iv, Q3W) and ifosfamide (1200 mg/m 2 , iv, Q3W) for a total of 4 cycles. The primary endpoint is the rate of pathologic complete response (pCR). Secondary endpoints are event-free survival, overall survival, objective response rate, disease control rate and safety. On the basis of a threshold pCR rate of 13.6%, targeting an expected pCR of 34% and assuming 12 months follow-up, 80% power and a one-sided α = 0.05, this design requires 34 evaluable patients to be accrued over 3 years. Clinical trial information: ChiECRCT20210503.